The purpose of the experiments proposed is to delineate determinants of the rates of metabolism in liver of lipophilic drugs, toxins, and environmental pollutants. Advances in our comprehension of these processes is related to better understanding of the molecular properties of purified enzymes that metabolize drugs and toxins. This work, however, has ignored the problem of how lipophilic xenobiotics reach their sites of metabolism within cells and whether these transport processes affect rates of metabolism. We have identified 3 metabolically significant aspects of the interrelations between the metabolism of lipophilic xenobiotics and the movement of these compounds within liver cells (1) We will determine whether the pool of xenobiotic substrates in equilibrium with the enzymes of xenobiotic metabolism (E + S approximately E.S) is the pool bound to intracellular membranes or in the aqueous phase. This is an important question because the former is concentrated and the latter is exceedingly dilute, and because the results of such investigations will have importance in formulating testable ideas about the routes of intracellular transport of lipophilic xenobiotics. (2) We will investigate whether the putative intracellular carrier proteins for lipophilic xenobiotics have the requisite properties for facilitating their transport within cells. (3) We also will study a model system in which lipophilic xenobiotics can move within cells without entering the aqueous phase in the cell. The experimental approaches are to determine rates at which membrane-bound lipophilic compounds leave the membrane to enter water and the relationship of this to rates of metabolism of the xenobiotic by membrane-bound and soluble enzymes of drug metabolism. We will examine the ability of intracellular transport proteins to interact directly with the membrane-bound xenobiotics an to compete with membranes for sequestering the xenobiotic, that is, to act as storage "depots" for toxic xenobiotics. we also will study rates of transfer of suitable probes between lipid vesicles. We believe these studies will improve our understanding of the mechanism for metabolic inactivation and disposal by the liver of endogenous and exogenous chemicals, which we believe will add to our knowledge of the basic biology of liver function and the derangements of function in patients with liver disease.